Dissertations / Theses on the topic 'Bone fragility'

Abstract The current benchmark for the assessment of fracture risk is the status of osteoporosis based on the measurement of bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA). However, DXA-based BMD has been shown to lack predictive ability for individual fracture risk. More than half of the hip fractures occur among people who are not classified as having osteoporosis. Osteoporosis (i.e. reduced bone mass) is only one risk factor for a fracture. In addition to bone mass, the mechanical strength of a bone is influenced by material and structural factors. However, we have limited information about the combined effects of BMD and bone structural properties in the evaluation of fracture risk, with regard to different types of hip fractures in particular. Therefore, this study investigated the radiograph-based structural factors of the upper femur for the assessment of bone mechanical competence and cervical and trochanteric hip fracture risk. The subjects of the clinical study comprised 74 postmenopausal women with non-pathologic cervical or trochanteric hip fracture and 40 age-matched controls. The impact of bone structure on the bone mechanical competence was studied using the experimental material of 140 cadaver femurs. The femora were mechanically tested in order to determine the failure load in a side impact configuration, simulating a sideways fall. In all study series, standard BMD measurements were performed, and the structural parameters of bone were determined from digitized plain radiographs. The present study showed that the large variation in the mechanical competence of bone is associated with the geometrical and architectural variation of bone. Moreover, the results strongly suggested that the etiopathology of different types of hip fractures significantly differs, and that fracture risk prediction should thus be performed separately for the cervical and trochanteric hip fractures. Furthermore, the study implied that the current clinical procedure can better be used for the assessment of the risk of trochanteric fracture, whereas cervical fracture is more strongly affected by the geometrical factors than by BMD. Finally, radiograph-based structural parameters of trabecular bone and bone geometry predicted in vitro failure loads of the proximal femur with a similar accuracy as DXA, when appropriate image analysis technology was used. Thus, the technology may be suitable for further development and application in clinical fracture risk assessment.

Current therapies for bone fragility disorders such as Osteogenesis Imperfecta (OI) can reduce fracture risk by improving bone quantity but not bone quality. Cell and/or gene therapy strategies hold promise for addressing the fundamental deficiencies in genetic bone disease but involve a number of technical hurdles that need to be overcome. This thesis takes a stepwise approach to address some of these challenges. Allogenic bone marrow transplantation (BMT) from healthy donors has been suggested for several decades to be able to repopulate the bone compartment with genetically healthy cells. However prior attempts have often featured poor osteoblastic engraftment. We describe the application of cell therapy to the mild-moderate severity Col1a2G610C OI mouse model. The effects of sub-lethal irradiation followed by transplantation of BMT from wild type (WT) mice into OI mice were analysed via DEXA, microCT, and mechanical testing. No differences were observed between the OI transplanted with WT cell group and the naïve WT and OI control groups in any measure. OI cells transplanted into OI mice were also included an additional control group to test for the paracrine effects of BMT, but again no significant differences were found compared to naïve OI controls. Lineage tracking using mice irradiated then transplanted with fluorescently labelled bone marrow cells revealed that most engrafted donor cells expressed the osteoclast marker tartrate-resistant acid phosphatase (TRAP). These results together indicate the inefficacy of irradiation and BMT on the osteopoietic compartment and suggest that alternative novel methods would be needed to increase engraftment for OI. In order to facilitate gene therapy approaches for OI, we aimed to engineer a system allowing the specific targeting of bone cells (osteoblasts and osteocytes) throughout the skeleton. Adeno associated viruses (AAVs) emerged as a prime vector candidate due to their small size, non-immunogenicity, and tissue specificity. A panel of 18 AAV variants expressing Cre recombinase and GFP under CAG ubiquitous promoter were first trialled via local delivery in a murine fracture model and in vitro on a human osteoblastic cell line. High performing variants, AAV8 and AAV-DJ were then used in systemic delivery experiments where vectors driving Cre expression via bone-cell specific promoters were designed and generated. The AAV8-Sp7-Cre vector was demonstrated to specifically and efficiently transduce osteoblasts and osteocytes throughout the skeleton. In a final series of experiments, delivery methods for the Cre constructs were compared and CRISPR/Cas9 gene editing constructs were designed and generated based on the Cre constructs design. Intraperitoneal (IP) delivery of the AAV8-CAG-Cre construct showed a similar transduction profile to intravenous (IV) delivery throughout the organs and bones. The one exception was skeletal muscle where IP delivery was able to transduce some skeletal muscle surrounding the tibia. In utero delivery was also trialled via IV delivery to pregnant female mice at ED17. This did not result in transduction of the pups, and IP injection of the pregnant female mice or direct injection of the pups in utero should be trialled. Finally, two AAV8 CRISPR/Cas9 constructs (a self-assembling intein system) able to drive gene editing of the Ai9 locus were produced. Preliminary studies showed a lack of gene editing in target tissues, and hence further studies were conducted to troubleshoot the constructs. HEK293 cells transduced with the virus in vitro showed staining of the N-terminal Cas9 intein, however the C-terminal Cas9 intein has yet to be validated. Further studies will be taken to resolve issues with these constructs to produce vectors able to mediate global skeletal gene editing in the Ai9 mouse. In summary, the published papers and subsequent experiments detailed in this thesis represent a stepwise approach for developing a gene therapy solution to genetic bone diseases. The creation of a bone specific Cre expressing AAV vector is expected to have remarkable utility as a tool for generating timed bone specific knockouts in floxed mouse lines. Its specificity and efficiency are particularly notable features. It is anticipated that rectification of one or more of the components of the split CRISPR/Cas9 approach will ultimately enable high-efficiency gene editing in bone, which will be a major advance for the field.

Osteoporosis is a significant healthcare issue due to the increasing elderly population. Bisphosphonates are used to treat osteoporosis by reducing the rate of resorption, increasing bone mineral density (BMD) and thereby reducing fracture risk. Long-term bisphosphonate treatment, however, has been associated with low-energy fractures. Bone microdamage may provide a partial explanation for one of the mechanisms responsible for these fractures since it has been shown to reduce bone toughness, fracture resistance, and bone strength. The goal of this study was to quantify the changes in bone microdamage parameters with the duration of bisphosphonate treatment. This study selected, stained, and histomorphometrically analyzed 40 iliac crest bone biopsies from controls and female patients with osteoporosis treated with bisphosphonates for varying durations (up to 12 years). All subjects were matched for age and low turnover. The results showed that microcrack density and microcrack surface density were significantly greater in patients who took bisphosphonates for at least 5 years compared to those who took bisphosphonates for less than 5 years or not at all. These results reveal novel, clinically relevant information linking microdamage accumulation to long-term bisphosphonate treatment without influences from age or turnover.

Vertebral fragility fractures are common, affecting approximately 50% of all postmenopausal women and 33% of men over the age of 50, and are the most common type of fracture seen in osteoporosis. The management of vertebral fragility fractures in the acute care setting is lacking in standardization, in the use of evidence-based practice, and in addressing the underlying cause of osteoporosis. The purpose of this project was to develop an evidence-based protocol to standardize the care of the vertebral fragility fracture in the acute care setting. This protocol included patient education, fall risk assessment, screening for osteoporosis, and follow up with an osteoporosis clinic for comprehensive management once discharged. This project used the Donabedian model to provide a conceptual framework for evaluating the structure, process, and outcomes related to the practice problem. This quantitative study involved 10 participants that were selected using purposive sampling and used process control charting to show compliance with elements of the guideline, and descriptive data to depict process change. Guideline compliance was measured over an 8-week period and indicated successful implementation of fall risk assessment with a 100% compliance rate and osteoporosis screening with an 80% compliance rate. Compliance with fracture education and securement of follow up were difficult to ascertain in the 8-week period and non-compliance evident. In conclusion, two elements of the guideline showed to be an unstable process and further work is necessary to improve. Positive social change may result from empowering nurses by education and giving them autonomy to use evidence-based practice to decrease the risk for secondary vertebral fragility fractures.

L’obésité est une pandémie qui ne cesse de progresser dans le monde. Elle entraîne avec elle de nombreuses maladies associées comme le diabète et diminue la fertilité. Malgré différente approche possible pour lutter contre l’obésité, la méthode la plus efficace reste la chirurgie bariatrique. Le nombre de chirurgie bariatrique augmente chaque année, notamment chez les femmes jeune en âge d’avoir des enfants. La chirurgie la plus pratiquée est la gastrectomie longitudinal (VSG). Les retentissements de la chirurgie bariatrique ne sont pas tous positifs, il a été montré dans différentes études que cela engendrait une perte de masse osseuse qui pourrait conduire à une fragilité osseuse. Peu d’étude ont été réalisées sur l’effet d’une grossesse à la suite d’une VSG et de son impact osseux à la fois pour la mère et pour les descendants. Dans un premier temps, dans un modèle de rat femelle nourrit avec de la nourriture riche en graisse et en sucre nous avons réalisé une VSG avant une gestation et une période de lactation. Nous avons mis en évidence une fragilité osseuse uniquement due au régime alimentaire et à l’obésité bien que les animaux aient perdu beaucoup de masse osseuse après la chirurgie, ils semblent capables de récupérer après la période de gestation/lactation. Dans un second temps, nous avons suivi les descendants mâle et femelle de ces animaux pendant 52 semaines. Malgré une différence de tailles à la naissance pour les mâles et les femelles, nous avons mis en évidence une fragilité osseuse uniquement chez les femelles descendantes de mère ayant subi une VSG. Cette différence est principalement due à une modification de la microarchitecture trabéculaire et corticale. Des études supplémentaires sont nécessaires afin de mieux comprendre l’origine de ces fragilités et de pouvoir proposer un suivi et un traitement adapter pour ces descendants afin de limiter l’apparition d’une fragilité osseuse au cours du temps
Obesity is a pandemic that continues to progress worldwide. It leads to numerous associated diseases, such as diabetes, and decreases fertility. Despite various possible approaches to combat obesity, the most effective method remains bariatric surgery. The number of bariatric surgeries increases every year, especially among young women of childbearing age. The most commonly performed surgery is the vertical sleeve gastrectomy (VSG). The effects of bariatric surgery are not all positive : it has been shown in several studies that it results in a loss of bone mass, which could lead to bone fragility. Few studies have been conducted on the effect of pregnancy following VSG and its impact on bone health for both the mother and the offspring. First, using a female rat model fed with high-fat, high-sugar diet, we performed a VSG prior to gestation and a lactation period. We observed bone fragility due solely to the diet and obesity. Although the animals lost significant bone mass after surgery, they seemed capable of recovering after the gestation/lactation period. Second, we followed the male and female offspring of these animals for 52 weeks. Despite a difference in size at birth between males and females, we observed bone fragility only in the female offspring of mothers that had undergone VSG. This difference is mainly due to changes in trabecular and cortical microarchitecture. Further studies are necessary to better understand the origin of these fragilities and to propose appropriate monitoring and treatment for these offspring, in order to limit the onset of bone fragility over time

Skeletal fragility is characterized by low bone mass, negative changes in bone microarchitecture, and compromised tissue matrix properties, including accumulation of microdamage. Microdamage accumulates in vivo from daily physiological loading and is targeted for repair through a normal remodeling process, thus preventing microcrack growth and potential fracture. However, impaired remodeling is associated with aging and osteoporosis, resulting in an increased accumulation of microdamage which contributes to reduced bone mechanical properties. The current clinical method for assessing increased risk of fracture involves measuring bone mineral density (BMD) of the hip and spine, locations of trabecular bone where high rates of remodeling occur. The bisphosphonate alendronate (ALN) reduces clinical risk for fracture by significantly increasing BMD, but studies have shown a concomitant reduction in intrinsic properties that may be the underlying cause for recent reports of spontaneous fractures with long-term alendronate use. Another anti-resorptive agent called raloxifene (RAL) is a selective estrogen receptor modulator (SERM) and has been shown to modestly improve BMD while decreasing fracture risk to a similar degree as alendronate. The combination of RAL and ALN as a treatment for osteoporosis may provide the benefits of each drug without the negative effects of ALN. Therefore, the overall goal of this thesis was to address the effects of aging and anti-resorptive agents on the properties of bone through the formation of microdamage. Assessment of age-related effects on bone was conducted through quantification of microdamage progression. It was found that old bone results in greater incidences of microdamage progression, reflecting a compromised tissue matrix with reduced resistance to crack growth. Effects of combination treatment with RAL and ALN were evaluated through biomechanical testing, micro-CT imaging, and microdamage quantification. Results showed improved trabecular bone volume and ultimate load with positive effects on trabecular architecture. Combination treatment reduced the proportion of microdamage that may lead to catastrophic fracture, indicating an improvement in the local tissue matrix properties.

In males, the widespread prevalence of both obesity-related metabolic syndrome (MetS) and testosterone deficiency (TD) is further exacerbating the socio-economic and health burdens already elicited by the rapidly ageing global population. The strong reciprocal relationship between the MetS and TD in males often results in their shared pathologies presenting together in the clinical setting. Clinical and epidemiological studies have provided convincing evidence that the MetS and TD are highly comorbid [1, 2] and share mutual abnormalities, including visceral obesity, dyslipidaemia and insulin resistance. One or more of these changes associated with the MetS and TD contribute to life-threatening conditions such as cardiovascular disease and increased osteoporotic bone fragility, particularly in the ageing male. Due to limitations of traditional androgen replacement therapy with testosterone (TEST), which is readily converted to active metabolites by enzymes, the therapeutic potential of trenbolone (TREN), a selective androgen receptor modulator (SARM), remains an attractive alternative to TEST. However, TREN’s efficacy has not been investigated in appropriate models representative of obese and TEST-deficient males, especially within the context of cardiometabolic disease and obesity-related osteoporosis/bone strength.
Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Medical Science
Griffith Health
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Abstract Ageing populations have made osteoporosis and fragility fractures a major public health concern worldwide. Half of all women and 30% of all men will suffer a fracture related to osteoporosis during their lifetime. While medical prevention of this immense problem is impossible at population level, it is necessary to find efficient preventive strategies. Exercise is one of the major prevention approaches because one reason behind the increasing burden of osteoporosis is the modern sedentary lifestyle. However, the optimal type, intensity, frequency, and duration of exercise that best enhances skeletal integrity are still largely unknown. We conducted a 12-month population-based randomized controlled exercise intervention in 120 premenopausal women. The aim was to investigate the effect of impact exercise on bone mineral density, geometry and metabolism in healthy women with the intention of assessing the intensity and amount of impact loading with a novel accelerometer-based measurement device. Training effects on risk factors of osteoporotic fractures, physical performance and risk factors of cardiovascular diseases were also evaluated. This study demonstrated that 12 months of regular impact exercise favoured bone formation, increased bone mineral density in weight-bearing bones, especially at the hip, and led to geometric adaptations by increasing periosteal circumference. Bone adaptations had a dose- and intensity-dependent relationship with measured impact loading. Changes in proximal femur were threshold-dependent, indicating the importance of high impacts exceeding acceleration of 4 g as an osteogenic stimulus. The number of impacts needed to achieve this stimulation was 60 per day. Impact exercise also had a favourable effect on physical performance and cardiorespiratory risk factors by increasing maximal oxygen uptake, dynamic leg strength and decreasing low-density lipoproteins and waist circumference. Changes were dose-dependent with impact loading at wide intensity range. Bone adapts to impact loading through various mechanisms to ensure optimal bone strength. The number of impacts needed to achieve bone stimulation appeared to be 60 per day, comparable to the same number of daily jumps. If done on a regular basis, impact exercise may be an efficient and safe way of preventing osteoporosis
Tiivistelmä Väestön ikääntymisen ja elintapojen muutosten myötä osteoporoosista ja osteoporoottisista murtumista on tullut maailmanlaajuinen terveysongelma. Ongelman laajuuden vuoksi murtumien lääkkeellinen ehkäisy ei ole mahdollista kattavasti väestötasolla, joten vaihtoehtoisten ehkäisymenetelmien kehittäminen on välttämätöntä. Liikunta on yksi potentiaalinen ehkäisykeino, koska yksi tärkeä tekijä ongelman taustalla on arkiliikunnan vähentyminen. Liikunnan tiedetään hyödyttävän luustoa, mutta optimaalisen liikunnan tyyppi, intensiteetti, määrä ja kesto ovat kuitenkin selvittämättä. Tämän tutkimuksen tavoitteena oli selvittää hyppyharjoittelun vaikutusta 35–40-vuotiaiden naisten luun tiheyteen, geometriaan ja aineenvaihduntaan sekä määrittää luun kannalta optimaalisen harjoittelun määrä ja voimakkuus. Tutkimuksessa selvitettiin myös harjoittelun vaikutuksia fyysiseen suorituskykyyn, sekä sydän- ja verisuonisairauksien riskitekijöihin. Toteutimme väestöpohjaisen, satunnaistetun, kontrolloidun 12 kuukauden mittaisen liikuntaintervention, johon osallistui 120 naista. Intervention aikana mittasimme hyppykuormitusten määrää ja voimakkuutta uudella kiihtyvyysanturiin perustuvalla menetelmällä. Nousujohteinen hyppyharjoittelu aiheutti kuormitetuissa luissa muutoksia, joista keskeiset olivat luuntiheyden ja luun ympärysmitan kasvu. Lisäksi luuston aineenvaihdunnassa tapahtui muutoksia, jotka osoittivat luun uudismuodostuksen lisääntyneen. Luun mukautumisen ja mitattujen iskukuormitusten välillä havaittiin annos-vastesuhde. Kuormitusten voimakkuus oli olennaista, sillä reisiluun kaulan luuntiheyden muutokset olivat yhteydessä kuormituksiin, joiden kiihtyvyys oli yli 4 kertaa maan vetovoiman (g) suuruinen. Luustomuutoksen saavuttamiseen tarvittavien kuormitusten määrä yli 4 g:n tasolla oli kuitenkin vain 60 kuormitusta vuorokaudessa, jotka voidaan turvallisesti saavuttaa normaaleilla hypyillä. Liikuntaharjoittelu paransi myös kolesteroliarvoja, maksimaalista hapenottokykyä, voimatasoja sekä pienensi vyötärön ympärystä, vaikuttaen näin positiivisesti sydän- ja verisuonisairauksien riskitekijöihin. Tutkimus osoitti luun mukautuvan muuttuneisiin kuormituksiin useiden mekanismien kautta ja mukautumisen olevan kuormitusten intensiteetistä riippuvaista. Osteoporoosin ehkäisyn kannalta tehokas ja turvallinen kuormitusmäärä näyttää olevan 60 hyppyä päivässä

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During the absence of load on the skeleton, and even short periods of reduced physical activity, may arise bone weakening. Thus, common medical treatments for diseases muscle-equeléticas involving immobilization through temporary splints, traction or rest forced the risk of fractures increase. Physical activity is studied, both to prevent damage and to promote recovery of bone structure. Therefore, the objective of this research was evaluated by bone densitometry and mechanical testing, the influence of hypocinesia and subsequent activity on a treadmill or free movement in femurs of rats. Sixty-four Wistar rats were used. The animals were created until the age of sixty-five days for the beginning of the procedures experimental. They were divided into eight groups, being three control and five experimental. The animals in group 6 (G6), were created until completeting 93 days of age and served as a control for G1, which was to suspend the animal by the tail for 28 days. In G7, the animals were created until 121 days and were for the control groups, G2 (suspended and trained on a treadmill for 4 weeks) and G4 (suspended and released for 4 weeks. Already in the G8, the animals were created until 149 days and were for the control groups, G3 (suspended and trained on a treadmill for 8 weeks) and G5 (suspended and released for 8 weeks). We analyzed the content and bone mineral density of the left femur by bone densitometry. Another analysis related to mechanical properties of the middle third of the femur (maximum force necessary to break and stiffness). The suspension by the tail caused a decrease in bone mineral density, maximum strength and rigidity of the femur of animals. The training on a treadmill and free activity after suspension promoted the recovery of bone mineral content, density, increased bone stiffness and strength required to produce fracture in a similar way and over time.
Durante a ausência de carga no esqueleto, e mesmo em curtos períodos de atividade física diminuída, pode ocorrer enfraquecimento ósseo. Assim, tratamentos médicos comuns para doenças músculo-equeléticas que envolvam imobilização temporária por meio de talas, repouso forçado ou tração aumentam o risco de fraturas. A atividade física é a medida mais estudada, tanto para evitar danos quanto para promover recuperação da estrutura óssea. Portanto, o objetivo deste estudo foi avaliar, por meio da densitometria óssea e do ensaio mecânico, a influência da hipocinesia e posterior atividade de corrida em esteira ou movimentação livre na caixa em fêmur de ratos. Foram utilizados sessenta e quatro ratos Wistar com sessenta e cinco dias de idade e massa corporal média de 316,11 gramas. Eles foram separados aleatoriamente em oito grupos, sendo três controles e cinco experimentais. Os animais do grupo 6 (G6), foram criados até completarem 93 dias de idade e serviram de controle para G1, composto por ratos suspensos pela cauda por 28 dias. No G7, os animais foram criados até 121 dias e foram controle para os grupos, G2 (suspenso e treinado em esteira por 4 semanas) e G4 (suspenso e liberado por 4 semanas). No G8, os animais foram criados até 149 dias e foram controle para os grupos, G3 (suspenso e treinado em esteira por 8 semanas) e G5 (suspenso e liberado por 8 semanas). Foram analisados o conteúdo e a densidade mineral óssea do fêmur esquerdo por meio de densitometria óssea. Foram analisadas as propriedades mecânicas do terço médio do fêmur (força máxima de ruptura e rigidez). A suspensão pela cauda provocou a diminuição na densidade mineral óssea, na força máxima admitida e na rigidez do fêmur dos animais. O treinamento em esteira e a atividade livre na caixa após a suspensão promoveram recuperação do conteúdo mineral ósseo e da densidade mineral óssea e aumentou a rigidez óssea e a força necessária para produzir fratura de forma semelhante e ao longo do tempo.

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Fundação Oswaldo Cruz. Instituto Fernandes Figueira. Departamento de Ensino. Programa de Pós-Graduação em Saúde da Criança e da Mulher. Rio de Janeiro, RJ, Brasil
Introdução: O aumento na ocorrência de fraturas secundárias à fragilidade óssea representa um significativo problema de Saúde Pública, já que corresponde a um importante aumento na morbidade, mortalidade e nos custos de mulheres na pós menopausa. Objetivos: Avaliar os fatores relacionados à ocorrência de fraturas em mulheres pós-menopausa acompanhadas em uma unidade básica de saúde. Metodologia: Foi realizado um estudo de coorte prospectivo, na ilha de Paquetá/RJ no ano de 2011. Através do banco de dados já existente, as mulheres foram localizadas por telefonemas e comparecimento no hospital local. As pacientes selecionadas foram submetidas a um questionário estruturado de avaliação de fatores relacionados à fragilidade óssea. Resultados: A incidência de fratura por fragilidade óssea encontrada foi de 21%, tendo como sitio principal o antebraço com 13%. A idade média da população foi de 72 anos com DP ± 9,0. No grupo de pacientes fraturadas 50% tinham entre 65 e 79 anos sugerindo ser essa faixa etária mais susceptível as fraturas por fragilidade óssea. Das pacientes que tiveram a Ultrassonometria óssea de calcâneo alterado, 22 % tiveram fraturas nesse período. Foi calculado o RR= 1,13 (IC95%: 0,48 - 2,63). As pacientes que tiveram fraturas se mostraram com maior sobrepeso ou obesas (72,2%), com maior historia familiar de fratura de quadril (13,3%) e com maior diagnostico de osteoporose (47,1%) do que as pacientes sem fraturas (p valor>0,05). E 23,5% das pacientes acamadas por mais de dois meses sofreram alguma fratura, com p valor <0,05. Na correlação entre as variáveis idade, tempo de menopausa e IMC, foi evidenciada uma associação positiva entre a idade e o tempo de menopausa nos grupos de pacientes com e sem fraturas. Conclusão: Os fatores de risco para fraturas por fragilidade óssea encontrados ajudam a conhecermos o perfil da nossa população e termos subsídios para combater esse agravo.
Introduction: The increased occurrence of secondary fractures associated with bone fragility represents a significant Public Health problem since it leads to a considerable increase in morbidity, mortality and in health care costs for postmenopausal women. Objectives: To evaluate the factors related to the occurrence of fractures in postmenopausal women attended at a public health center. Methodology: A prospective cohort study was conducted in Paquetá Island, Rio de Janeiro, in 2011. Using an existing database, these women were identified, contacted by phone and asked to come to the local hospital. The selected patients were submitted to a structured questionnaire assessing factors related to bone fragility. Results: The incidence of fracture due to bone fragility was of 21%, and the main site was the forearm, accounting for 13%. The average age of the population was 72 with a SD ± 9.0. In the group of fractured patients, 50% were between 65 and 79 years old, which suggest this is the age group that is most susceptible to fractures associated with bone fragility. Twenty two percent of the patients who had an altered quantitative ultrasonometry of the calcaneus had fractures in that period of their lives. The RR was calculated: RR = 1.13 (CI 95%: 0.48 – 2.63). The patients who had fractures were more overweight or obese (72.2%), had a longer family history of hip fracture (13.3%) and more diagnoses of osteoporosis (47.1%) than patients without fractures (p-value > 0.05). And 23.5% of the patients who were bedridden for more than two months suffered some type of fracture, with a p-value < 0.05. In the correlation between the different ages, time of menopause and BMI, a positive association between age and time of menopause became clear in the groups of patients with and without fractures. Conclusion: The risk factors for fractures associated with bone fragility help us to define the profile of our population and provide us with means to fight this problem.

La microarchitecture osseuse est un des déterminants de la qualité osseuse qui peut maintenant être évaluée in vivo au radius et au tibia distaux avec une résolution isotropique de 82μm par un nouveau scanner à haute résolution (XtremeCT, SCANCO Medical AG). Par ailleurs, l’utilisation d’analyse en éléments finis sur les volumes 3D obtenus permet d’évaluer les propriétés biomécaniques de l’os comme la résistance osseuse. Nous avons montré qu’il s’agissait d’une technique prometteuse pour évaluer la densité, la microarchitecture et les propriétés biomécaniques osseuses au niveau des sites périphériques, notamment parce que ces mesures étaient associées chez la femme avec des fractures ostéoporotiques de toutes sortes. Nous avons également montré que les mêmes mesures étaient tout aussi pertinentes chez l’homme, alors qu’il est moins sujet à l’ostéoporose. Les résultats étaient associés aux fractures ostéoporotiques de toutes sortes, notamment les fractures vertébrales. L’analyse en éléments finis permet donc la mesure in vivo de la résistance osseuse, ce qui pourrait fournir des informations sur la fragilité osseuse et le risque de fracture non accessible par les seules mesures de densité ou de microarchitecture osseuse
Bone microarchitecture is one of the determinants of bone quality that can now be evaluated in vivo at the distal radius and tibia with an isotropic resolution of 82μm with a new high-resolution peripheral scanner (XtremeCT, SCANCO Medical AG). Moreover, the use of finite element analysis on the 3D bone volume acquired allows the assessment of bone biomechanical properties such as bone strength. Our studies show that this technique is promising to assess bone density, microarchitecture and strength at peripheral skeletal sites. Indeed those measures were associated with osteoporotic fractures of all kinds in women. We also demonstrated that those same measures were associated with osteoporotic fractures of all kinds, including vertebral fractures, in men, who are less prone to be affected by osteoporosis. Finite element analysis allows in vivo measurement of bone strength, which might provide additional information about bone fragility and fracture risk that are not assessed by measures of density or microarchitecture

L'obésité est un facteur de risque majeur de diabète de type 2 (DT2), favorisés par une inflammation systémique et une résistance à l'insuline. Ces pathologies métaboliques sont associées à une fragilité osseuse augmentant significativement le risque de fracture souvent sans modification de la masse osseuse. Elles s'accompagnent aussi d'un niveau de graisse dans la moelle osseuse (adiposité médullaire (AM)) anormalement élevé et suspectée de jouer un rôle délétère sur l'os. Cependant, les mécanismes responsables de l'accroissement de l'AM et ses conséquences sur l'os sont encore mal définis. Les défensines et la cathélicidine, des peptides antimicrobiens de l'immunité innée dont l'expression est modifiée dans l'obésité et le DT2, semblent influencer la différenciation ostéoblastique de cellules souches squelettiques (CSS). Cette thèse explore les relations entre l'expression du gène de la cathélicidine, la régulation de l'AM, et les altérations osseuses dans les contextes d'obésité et de DT2. La première partie de ce travail a évalué, dans des modèles murins d'obésité (basé sur un régime riche en lipides, High Fat Diet-HFD) et de DT2 (HFD associé à un traitement par streptozotocine-STZ), les relations entre l'expression de la cathélicidine murine (CRAMP : cathelicidin-related antimicrobial peptid), l'AM, la microarchitecture et la fragilité osseuse. Les souris C57BL/6J mâles soumises à un régime HFD développent une obésité hyperinsulinémique, caractérisée par un gain de poids, une hyperglycémie modérée, une intolérance au glucose et une insulino-résistance. Cette obésité a induit une réduction de l'épaisseur trabéculaire et corticale du tibia, associée à une expansion significative de l'AM, sans modification des taux circulants du peptide CRAMP malgré une baisse de l'expression de ses transcripts dans le tissu adipeux viscéral (TAV). Ces observations soulignent un effet de l'insuline sur l'accumulation des adipocytes médullaires (AdMeds). En revanche, le modèle HFD/STZ induit une hyperglycémie et une insulinopénie marquées, caractéristiques d'un DT2, limitant l'expansion des graisses périphériques et médullaires par rapport aux souris HFD. Ces souris diabétiques présentent une fragilité osseuse accrue, avec une réduction du nombre de trabécules de tibia et une baisse de rigidité de l'os cortical fémoral, associées à des taux réduits de CRAMP circulant. Cela suggèrent une corrélation entre la diminution de CRAMP circulant dans le DT2 et une qualité osseuse compromise à l'origine de la fragilité osseuse des souris diabétiques. Dans la deuxième partie de cette thèse, nous avons étudié in vitro l'expression du gène de la cathélicidine humaine (CAMP) dans les AdMeds différenciés à partir de CSS, et sa régulation par divers stimuli métaboliques. Pour la première fois, nous avons détecté l'expression des transcrits de CAMP dans les AdMeds dès le jour 3 de différenciation, avec une augmentation linéaire jusqu'à maturité des AdMeds au jour 21. En présence de fortes concentrations de glucose (11 ou 25 mM), le taux d'ARNm de CAMP est significativement réduit dans les AdMeds, ce qui corrobore la corrélation négative observée entre CRAMP circulant et la glycémie des souris diabétiques. En outre, le traitement des AdMeds différenciés avec du butyrate ou de l'oléate a entraîné une augmentation des ARNm de CAMP, tandis que le propionate a induit un effet inverse. Ces régulations suggèrent que les taux altérés d'acides gras libres dans les contextes d'obésité/DT2 ou de fragilité osseuse peuvent impacter la sécrétion de CAMP dans le plasma et la moelle osseuse. Ce travail de thèse suggère que l'expression systémique de CAMP pourrait constituer un marqueur immuno-métabolique de la fragilité osseuse associée au DT2. D'autres études sont nécessaires pour préciser les mécanismes régulant l'expression de la cathélicidine en contextes d'obésité et de DT2 et mieux comprendre son rôle dans la régulation de l'AM et de la qualité osseuse
Obesity is a major risk factor for developing type 2 diabetes (T2D), the diseases favoured by systemic inflammation and insulin resistance. These metabolic diseases are associated to bone fragility increasing significantly the risk of fracture, often without modification in bone mineral density. Obesity and T2D are also accompanied by an abnormal high level of fat in the bone marrow (bone marrow adiposity (BMA)) which is suspected to exert a deleterious effect on the bone. However, the underlying mechanisms increasing the BMA and its consequences on bone tissue are not fully understood. The defensins and the cathelicidin, the antimicrobial peptides of the innate immunity the expression of which is modified in obesity and T2D, seem to influence the osteoblastic differentiation of skeletal stem cells (SSC). This PhD thesis explores the relationships between the expression of the cathelicidin gene, the regulation of BMA, and the bone alterations in the context of obesity and T2D. The first part of this work evaluated, in murine models of obesity -based on High Fat Diet - HFD) and of T2D (induced by HFD combined with streptozotocin-STZ treatment), the relations between the expression of the murine cathelicidin (CRAMP : cathelicidin-related antimicrobial peptide), the BMA, and bone microarchitecture and fragility. C57BL/6J male mice fed with HFD have developed hyperinsulinemic obesity, characterized by weight gain, a moderate hyperglycaemia, an impaired glucose tolerance with an insulin resistance. This obesity induced decreased trabecular and cortical thickness of the tibia, associated with a significant expansion of BMA, without changes in the circulating levels of the CRAMP peptide despite a decreased expression of its transcripts in visceral adipose tissue (VAT). These findings highlight the role of insulin in the accumulation of bone marrow adipocytes (BMAds). In contrast, the HFD/STZ mice model induces a marked hyperghycemia and insulinopenia, features of T2D, limiting the expansion of both peripheral and marrow fat as compared to the HFD group. The HFD/STZ diabetic mice also exhibit increased bone fragility, as characterized by a reduction in the trabeculae number of the tibia and a decrease of cortical rigidity of the femur, associated with decreased of CRAMP circulating levels. These alterations suggest a correlation between declined serum levels of CRAMP with a compromised bone quality leading to the bone fragility in diabetic mice. In the second part of this thesis, we studied in vitro the expression of the human cathelicidin gene (CAMP) in BMAds differentiated from SSC, as well as its regulation in response to various metabolic stimuli. For the first time to our knowledge, this study detected the expression of CAMP transripts in BMAds as early as the third day of differentiation, with a gradual increase until mature adipocytes on day 21. Under high glucose concentration (11 or 25 mM), the mRNA levels of CAMP are significantly reduced in BMAds, thus corroborating the negative correlation observed between circulating CRAMP and glycaemia in diabetic mice. Furthermore, treatment of differentiated BMAds with butyrate or oleate led to an increase in CAMP transcripts, whereas propionate caused an opposite effect on CAMP expression in vitro. These regulations suggest that abnormal levels of free fatty acids in the contexts of obesity and T2D or of bone fragility, may have effects on plasma and bone marrow levels of CAMP. Although further studies are needed, this thesis work suggests that the systemic expression of CAMP could constitute an immune-metabolic marker of bone fragility related to T2D. Future research is essential to clarify the mechanisms regulating the cathelicidin expression and better understand its role in the regulation of BMA and bone quality in the contexts of obesity and T2D

Background: Older people presenting with hip fractures requiring surgery have a high prevalence of hypovitaminosis D, which is an important modifiable risk factor for falls and fractures. Inadequate sun exposure is the main reason for vitamin D deficiency in older people. Vitamin D supplements, with or without calcium have been shown to reduce falls and fracture risk in this population. Undertreated pain is a risk factor for delirium and a barrier to rehabilitation interventions following a hip fracture. A small number of randomised controlled trials (RCTs) have shown increased 25-OHD levels with a loading dose of vitamin D may improve falls and fractures. Low vitamin D levels have also been implicated in pain generally, as well as static and dynamic pain responses to mobility. It is not known whether oral vitamin D replenishment using a loading dose is effective, and if it is, what is the interplay this is with patient characteristics, in particular self-reported pain rating levels, lower limb mobility and 25-OHD levels. Aims: The aims of this research were (1) to characterise the predictive factors of 25-OHD levels; (2) to characterise the predictive factors of self-reported pain after hip fracture; (3) to determine the benefit of early loading-dose oral vitamin D replenishment and determine the 25-OHD response; (4) to evaluate safety profile of an initial high-dose (250,000IU) vitamin D followed by daily maintenance for 6 months; (5) to monitor its effects on functional mobility, falls, fractures, grip strength, health related quality of life and mortality. Methods: Participants of the REVITAHIP RCT cohort (mean age of 220 participants was 83.9 (SD 7.2) years and 77.1% were women): Active (111) and Placebo (107) participants were randomised to loading dose (250000IU vitamin D3) vs placebo followed by 6 months maintenance oral therapy (vitamin D3/calcium: 800IU/600mg) daily. Primary outcome measures are 2.4m gait-velocity, with secondary outcome measures of falls, fractures (Week-4), 25-OHD levels, quality-of-life measure (EQ-5D), mortality at weeks-2, 4 and 26 with additional measures of pain (via the numerical rating scale [NRS]) were correlated with patient characteristics in this cohort. Results: Hypovitaminosis D (25-OHD <50nmol/L) was present in 46.8% of participants and 15.4% had 25-OHD levels lower than 30nmol/L. Multivariate regression models demonstrated higher baseline vitamin D levels were significantly associated with higher premorbid Barthel Index scores and lower post-operative NRS pain levels. Further, the mean (SD) NRS pain score was 3.5 (2.3). More than half (61.9%, n=113) had NRS>3 and 18.1% (n=52) had NRS>5. Using the EQ-5D pain sub-score, 78.1% had moderate pain or discomfort and 7.9% had extreme pain or discomfort. Using a multivariate regression model, postoperative NRS was significantly higher in persons with a higher comorbidity count, those previously living independently alone, and surgical fixation with hemiarthroplasty. After loading dosing administration, 25-OHD levels were significantly higher for the Active group when compared to the Placebo group at 2 weeks (73 vs 66 nmol/L; p=.019) and at 4 weeks (83 vs 75nmol/L; p=.030). At week 4, the Active group had a significantly lower percentage of people with suboptimal 25-OHD levels (3.2% vs 15.4%, p=.019). At week 4, participants in the Active group had a gait velocity over 2.4m of 0.42m/s compared with 0.39m/s in the placebo group (p=.490). To week 4, seven (6.3%) participants in the Active group reported 1 or more falls compared to twenty-three (21.1%) in the Placebo group (χ2 = 4.327; p=.024) but there were no differences in fractures (2.7% vs 2.8%, p=.964) or grip strength. The number of deaths was non-significantly lower in the Active group compared with the Placebo group at 4 weeks (1 vs 3, p = .295). There was a trend for Active participants to have a higher total EQ-5D scores at Week 26 (88.1+/-13.2 vs 84.3+/-15.8, F=2.87, p=.092). Active participants were significantly more likely to present with ‘no pain or discomfort’ at Week 26 (96.4% vs 88.8%, p=.037). One case of hypercalcemia at 2 weeks was noted in the Active group which normalised after 4 and 26 weeks. Discussion and Conclusions: This study cohort shared similar demographic characteristics and comorbidities with other cohorts of people with hip fracture. Hypovitaminosis D was not as prevalent as previously documented. Patients taking vitamin D supplements and with higher premorbid Barthel Index, reflecting greater independence and activity, tended to have higher 25-OHD levels at baseline. Further, lower NRS pain ratings following surgery were associated with higher vitamin D levels. Overall, the levels of pain reported by this cohort are acceptable although approximately 10% to 15% had higher than reasonable levels of pain. Despite a higher than expected baseline 25-OHD level and moderate increases in 25-OHD levels, participants in the Active REVITAHIP group resulted in a greater percentage with target 25-OHD levels (>50nmol/L) compared with the placebo group with no significant differences in gait velocity at 4 weeks. Lower numbers of falls and improved pain control were noted in the Active group over the study period. In this cohort, there was a higher than expected baseline 25OH level which could have underestimated the effect of the intervention in a group with lower baseline 25-OHD levels.

S'han identificat els casos de fractura per fragilitat atesos en el servei d'urgències de la Corporació Sanitària i Universitària Parc Taulí de Sabadell. Per a les fractures de fèmur i pelvis s’han comparat les exposicions farmacològiques amb les de controls procedents del mateix entorn geogràfic. L'estudi s'ha desenvolupat en dues fases: una inicial amb controls triats al mateix servei d'urgències, que va concloure una manca de validesa interna de l'estudi per probable biaix de selecció, i una segona fase en la que els controls es van identificar a partir dels registres sanitaris d'atenció primària de la mateixa àrea geogràfica d'influència de l'hospital, emprant les dades de l’història electrònica d'atenció primària. En aquesta segona fase, s'ha conclòs una validesa interna del disseny acceptable mitjançant la reproductibilitat de l'observació dels riscos associats a la utilització de corticoides, que han estat àmpliament descrits prèviament en diversos entorns. Per a les exposicions d’interès que eren l’objectiu del present estudi, s'han observat increments de risc significatius associats a l'exposició crònica a inhibidors de la bomba de protons i a antidepressius inhibidors selectius de la recaptació de serotonina. Tanmateix, s’hi han observat increments de risc associats a l'exposició a antagonistes de la vitamina K, diürètics de nansa, agonistes beta-2 adrenèrgics selectius inhalats, anticolinèrgics inhalats i antiagregants plaquetaris.
Cases of fragility fractures have been identified at the emergency room of the Corporació Sanitària i Universitària Parc Taulí de Sabadel. Cases of femur and pelvis fractures have been selected and compared to controls from the same geographical area in respect to medication exposures. The study was developed in two phases, with an initial phase where controls were identified at the same emergency service than cases, which concluded a lack of internal validity of the study likely due to selection bias. A second phase identified the controls from medical records of primary health care in the same geographic area of influence of the hospital, using data from the primary care electronic record. This second phase has concluded an acceptable internal validity through reproducibility of the risks associated with the use of corticosteroids, which have been widely described previously in various environments. Regarding the exposures of interest that were included as objectives of this study, increased risks have been observed associated to chronic exposure to proton pump inhibitors and selective serotonin reuptake inhibitors. Also, increased risks have been observed for exposures to vitamin K antagonists, loop diuretics, inhaled selective beta-2 agonists, inhaled anticholinergics and oral antiplatelet agents.

Le rôle de la microstructure trabéculaire et corticale dans la résistance osseuse et le risque de fracture est bien documenté mais son déterminisme génétique n’a pas encore été étudié. Pour savoir si la microarchitecture osseuse et le métabolisme osseux ont un déterminisme héréditaire, une étude épidémiologique transversale (étude MODAM) a été menée pour évaluer la ressemblance familiale de la microarchitecture osseuse chez les femmes ménopausées et leurs filles non ménopausées en utilisant la tomodensitométrie quantitative périphérique haute résolution (HR-pQCT). Nous avons constaté que les filles des femmes ayant subi une fracture ont une densité osseuse volumétrique totale (vBMD) plus faible, des corticales amincies, et une altération de la microarchitecture osseuse trabéculaire au niveau du radius distal et du tibia comparativement aux filles dont les mères n’ont pas eu de fracture. Une autre étude épidémiologique transversale (étude MINOS) a été menée pour évaluer la corrélation de la densité minérale osseuse (DMO), de la taille des os, des marqueurs du remodelage osseux (BTM) et des hormones de régulation du remodelage osseux dans des paires de frères et des paires d'hommes non apparentés, appariés pour l'âge, le poids et la taille. Nous avons constaté que la taille des os, la DMO à certains sites du squelette et la plupart des BTM étaient plus fortement corrélés chez les frères comparativement aux hommes non apparentés. Ces données suggèrent un déterminisme héréditaire substantiel des niveaux de BTM chez les hommes. En conclusion, nous développons et confirmons l'importance des facteurs familiaux dans la pathogénie de l'ostéoporose chez les femmes et les hommes
The role of trabecular and cortical microstructure in bone strength and fracture risk is well documented, but its genetic determinism has not yet been studied. To find whether the bone microarchitecture, and bone metabolism have a strong hereditary determinism, a crosssectional epidemiological study (MODAM study) was conducted, investigating the familial resemblance of bone microarchitecture in postmenopausal mothers and their premenopausal daughters using high-resolution peripheral quantitative computed tomography (HR-pQCT). We found that daughters of women with fracture have lower total volumetric bone mineral density (vBMD), thinner cortices, and impaired trabecular microarchitecture at the distal radius and tibia, compared with daughters of women without fracture. Another cross-sectional epidemiological study (MINOS study) was conducted to assess the correlation of bone mineral density (BMD), bone size, bone turnover markers (BTMs) and hormones regulating bone turnover in pairs of brothers and pairs of unrelated men, matched for age, weight and height. We found that bone size, BMD at some skeletal sites and most of the BTM levels correlated more strongly in the brothers than in the unrelated men. These data suggest a substantial hereditary determinism of the BTM levels in men. In conclusion, we expand and confirm the importance of familial factors in the pathogenesis of osteoporosis in both women and men

Geology
M.S.
In modern organisms the structure and arrangement of bone apatite crystals is dependent on the arrangement of the organic collagen fibers. This is reflected in the formation of different types of bone tissue, such as woven (immature) or lamellar (mature), in pathological versus normal bone, or fast-growing (woven) versus slow-growing (lamellar) tissue. Because the basic physiological processes of fracture healing are similar in extant vertebrates, similar patterns may exist in fossil taxa. The three questions of interest for this study were the following: 1) Do differences exist in modern bone apatite crystallinity between normal and pathologic bone? 2) Are differences between normal and pathologic tissue consistent in both modern and fossil bone? 3) Does the type of bone tissue affect fossilization? In this study, we use histological and x-ray diffraction (XRD) analyses to examine fracture pathologies in pedal phalanges from the theropod dinosaur Allosaurus fragilis, and two modern bird species, Branta canadensis (Canada goose) and Cathartes aura (turkey vulture). Raman spectroscopy analysis was performed on modern birds, but not fossil material. Stable isotope and rare earth elements (REE) analyses were performed on fossil material to determine if there are differences in how pathologic bone fossilizes compared to normal bone. Results from Raman spectroscopy and XRD confirm that pathologic bone is more crystalline than normal bone in both fossil and modern taxa. Stable isotope and REE analyses do not show any difference in fossilization between pathologic and normal bone, suggesting that these techniques are more suitable for examining taphonomic rather than physiological differences.
Temple University--Theses

La Communauté Economique des Etats d’Afrique de l’Ouest est une organisation internationale qui s’est très tôt impliquée dans le maintien de la paix et de la sécurité. Elle a entrepris des interventions militaires dans certains Etats ouest-africains, comme le Libéria, la Sierra Léone, la Guinée Bissau, dans les années 1990. A partir de 1999, la CEDEAO a procédé à une réorientation stratégique en matière de sécurité. Celle-ci s’est manifestée par l’adoption d’un nouveau mécanisme de sécurité visant à placer l’individu au cœur des préoccupations sécuritaires. Le nouvel objectif de la CEDEAO est de réaliser la sécurité humaine au profit des citoyens ouest-africains. Il se trouve que la réalisation de la sécurité humaine nécessite des moyens économiques et financiers, or les Etats ouest-africains sont parmi les plus pauvres du monde. Aussi, depuis l’adoption du nouveau mécanisme de sécurité, la CEDEAO rencontre de plus en plus de difficultés à concrétiser les nobles recommandations et principes contenus dans son ordonnancement juridique, dans un contexte marqué par l’accroissement des menaces militaires contemporaines et des menaces non militaires.Après plus de 30 ans d’expériences dans le processus d’intégration, n’est t-il pas désormais évident que la réussite de l’organisation dans le maintien de la paix et de la sécurité est intimement liée au progrès accompli dans l’intégration économique ? La faiblesse des perspectives économiques des Etats de la CEDEAO n’appelle-t-elle pas à modifier la stratégie d’intégration de la CEDEAO ? L’adoption du fédéralisme à l’échelle ouest-africaine ne peut-elle pas constituer une voie salvatrice pour la CEDEAO ?
The Economic Community of West Africa is an international organization that was involved very early in the peacekeeping and security. It undertook military intervention in some West African states, like Liberia, Sierra Leone, and Guinea Bissau. In 1999, ECOWAS has made a strategic shift in security. This was manifested by the adoption of a new security mechanism to place the human at the heart of security concerns. The new objective of ECOWAS is to achieve human security for the citizens of West Africa. It turns out that the realization of human security requires economic and financial means, or the West African states are among the poorest in the world. Also, since the adoption of the new security mechanism, ECOWAS meeting more and more difficult to achieve the noble principles and recommendations contained in its legal system, in a context of increased of contemporary military and non military threats. After over 30 years of experience in the integration process, is there not now clear that the success of the organization in peacekeeping and security is closely linked to progress in the economic integration? The weak economic outlook states of ECOWAS calls does not change the strategy of integration of ECOWAS? The adoptions of federalism across West Africa cannot it be a way of salvation for ECOWAS?

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2014
Introduction: Chronic Kidney Disease (CKD) is a worldwide health problem and disturbances in mineral metabolism are common complications of the disease, contributing to bone fragility. Along with CKD, Osteoporosis is also a very common disorder of aging populations. Moreover, with the normal aging process on the bone, there is an acceleration of the deterioration, prematurely diminution bone quality and strength and increased early susceptibility to fractures. Consequently, one of the major complications of CKD, especially in elderly patients, is also the increased risk of fragility fractures, which is well demonstrated in patients with end-stage renal disease (ESRD). Objective: the aim is to evaluate whether CKD, in stages before ESRD, is associated with bone fragility. Methods and Patients: We studied patients admitted for total hip replacement surgery. The patients who gave their informed consent, were asked for clinical data and blood samples. Blood biomechanical studies were performed and a bone cylinder was drilled from their femoral epiphyses. Glomerular filtration rate (GFR) was estimated using CKD-EPI equation. Results: We included 351 patients, divided in two groups: those with Osteoporosis (OP) and those with Osteoarthritis (OA) (control group). In the study group mean age was 78.98 ± 8.72, 80% were female. No association was found between existence of previous fragility fractures and estimated GFR (eGFR) or mechanical tests measures and eGFR both in OP and OA group (p> 0.05). Also, association between bone turnover markers (BTM) and eGFR was inexistence in the OP group. The biomarkers beta-crosslaps (CTX) and amino-terminal propeptides of type I procollagen (P1NP) showed an association with eGFR (p<0.05) in the OA group. Although we can’t state an association between CKD early stages and bone fragility with our results, and specifically with the indicators we used, further assessments should be done on the topic.
Introdução: A Doença Renal Crónica (DRC) é um problema de saúde pública a nível mundial e as alterações no metabolismo mineral são complicações comuns desta doença, contribuindo para a fragilidade óssea. Ao mesmo tempo, a Osteoporose é uma patologia comum na população mais envelhecida. Para além disso, com o processo normal de envelhecimento do osso, há uma aceleração da deterioração, levando a uma diminuição prematura da qualidade e plasticidade do osso, aumentando a susceptibilidade precoce a fracturas. Consequentemente, uma das complicações major da DRC, em particular nos doentes idosos, é também o aumento do risco de fracturas de fragilidade, que está bem demonstrado nos estádios terminais da DRC. Objectivo: Avaliar se a DRC, em estádios anteriores a doença terminal, está associada a fragilidade óssea. Método: Foram estudados doentes admitidos para cirurgia de substituição total da anca. Foi-lhes aplicado um questionário e colhidas amostras de sangue. Estudos bioquímicos no sangue foram realizados e foi retirado um cilindro de osso das epífises femorais. A taxa de filtração glomerular (TFG) foi estimada utilizando a fórmula CKD-EPI. Resultados: Foram incluídos 351 doentes, que se dividiram em dois grupos: doentes com Osteoporose (OP) e doentes com Osteoartrite (AO) (grupo controlo). No grupo de estudo a idade média foi 78.98 ± 8.72 e 80% eram do sexo feminino. Nenhuma associação foi encontrada entre existência de fracturas prévias e a TFG estimada (eTFG), bem como entre os testes mecânicos e a eTFG, tanto no grupo da OP como na OA. Também entre marcadores de remodelação ósseos (MRO) e a eTFG não foi encontrada associação no grupo OP. Os MRO: beta-crosslaps (CTX) e pro-péptidos de terminal amino de colagénio tipo 1 (P1NP) demonstraram uma associação entre a eTFG no grupo OA. Apesar de não ser possível afirmar uma associação entre DRC nos estádios precoces e fragilidade óssea com os nossos resultados, e especificamente com os indicadores utilizados, outros estudos devem ser realizados sobre este tópico.

The function of skeletal adaptation to mechanical load is to adjust the amount and distribution of bone tissue (geometry); such that stresses experienced within the bone are kept within certain physiological limits and fractures are prevented. Genetic, environmental or hormonal factors may cause heterogeneity in this adaptive response, altering geometry and consequently fragility. The purpose of this thesis was to explore the skeletal response to load in vivo, by evaluating stress at the hip under three different conditions: FRACTURE (Study 1), DIABETES (Study 2) and ESTROGEN deficiency (STUDY 3). We studied women 25 years of age or older who participated in the Canadian Multicentre Osteoporosis Study and had available Hip Structure Analysis (HSA) data from baseline dual energy x-ray absorptiometry (DXA) scans. Women were categorized according to fracture status (fracture or no fracture), diabetes status (diabetes or no diabetes) and estrogen use (current users or never users). We computed stress (megapascals=MPa) at the infero-medial margin of the femoral neck in a one-legged iii stance using a 2-D engineering beam analysis. We used linear regression to determine associations between femoral neck stress and each categorical variable. Study 1 (n=2168) demonstrated higher stresses in postmenopausal women with fractures compared to women without fractures (10.57 ± 2.19 vs. 10.30 ± 2.03 MPa; p=0.0031). Study 2 (n=3665) demonstrated higher stresses in women with Type 2 Diabetes Mellitus compared to non-diabetic women (10.98 ± 2.33 vs. 10.57 ± 2.20 MPa; p=0.0194). Study 3 (n=2447) demonstrated higher stresses in postmenopausal women not on estrogen than in premenopausal women (10.66 ± 2.14 vs. 10.09 ± 2.01 MPa; p<0.0001), but no differences in stresses between postmenopausal women on estrogen and premenopausal women (10.16 ± 2.00 vs. 10.09 ± 2.01 MPa; p=0.6102). Since stress is an indicator of underlying geometry, and geometry should be adapted to prevalent loads, higher stress indicates weaker geometry and suggests an impaired modeling response in these three conditions. Compromised modeling has important clinical implications in terms of treatment selection, as individuals with reduced load sensitivity may respond best to metabolic agents that would improve modeling responses to load stimuli.

Mestrado em Integrado em Engenharia Biológica, Ramo de Tecnologia Química e Alimentar
Osteoporosis is a chronic skeletal disorder characterized by loss of bone mass and deterioration of the bone tissue, which leads to an increased risk of fractures. The aetiology of this disease resides on the impairment between bone resorption (conducted by osteoclasts) and formation (conducted by osteoblasts). Considering an ageing population, it is expected a steady rising number of cases over the next years, turning osteoporosis into a serious public health issue that represents a leading cause of morbidity and mortality, mainly due to the fragility fractures. Nowadays, the osteoporosis treatments consist predominantly in anti-resorptive drugs that inhibit/prevent bone resorption but are often associated with several side effects. Therefore, the need for new approaches to promote bone homeostasis and regeneration/repair of fragility fractures in patients with osteoporosis is increasing. Over the past years microRNAs (miRNAs), a class of small non-coding RNAs that coordinate virtually all cellular mechanisms through regulation of gene expression, have gained status as important post-transcriptional regulators. Recent studies revealed their pivotal role in the pathogenesis of several human diseases, including osteoporosis. In this context and following the previous results of a microRNA microarray, the main aim of this study was to investigate the role of miR-99a-5p in osteogenic differentiation and evaluate its expression during osteoclastogenesis, crucial processes required for bone formation and repair. Also, we aimed to determine its expression in fracture healing/repair process and fragility fracture samples. To achieve our aims, we first assessed miR-99a-5p expression profile during osteogenic differentiation in both MC3T3 cell line and primary human Mesenchymal Stem/Stromal Cells by reverse transcription – real-time quantitative polymerase chain reaction (RT-qPCR). Next, to analyze the biological effect of miR-99a-5p in osteogenesis and proliferation, we performed in vitro transfections of miR-99a-5p mimics and inhibitors. In an attempt to identify relevant mechanisms and pathways of action of miR-99a-5p we further analyzed the protein expression profile of anti-miR-99a-5p transfected cells compared to control. Furthermore, the expression profile of miR-99a-5p during osteoclastogenesis of RAW 264.7 cell line and human monocytes was investigated, as well as the effect of conditioned media from MC3T3 transfected cells on osteoclastogenesis. Finally, miR-99a-5p expression during the bone repair/regeneration process and in patients that suffered an osteoporotic fracture was determined. The results showed that miR-99a-5p was significantly down-regulated during MC3T3 osteogenic differentiation and during early stages of human primary MSC osteogenic differentiation. miR-99a-5p overexpression in pre-osteoblastic cell line MC3T3 led to a decrease of osteogenic differentiation markers, whereas its inhibition enhanced osteogenesis markers, including alkaline phosphatase expression and staining. However, modulation of miR-99a-5p levels in MC3T3 cells did not show to affect proliferation. Proteomic analysis on anti-miR-99a-5p transfected cells showed that numerous proteins known to be involved in osteogenic differentiation were altered, in comparison with the control, such as plexin-A2 (PLXA2), all-trans retinoic acid-induced differentiation factor (ARAID), ARF GTPase-activating protein GIT (GIT1) and Ephrin type-A receptor 2 (EPHA2). Furthermore, inhibition of miR-99a-5p levels were predicted to impact several pathways associated with osteoporosis, including Ephrin receptor, Pl3K-Akt and canonical Wnt pathways. In contrast to osteogenesis, miR-99a-5p was upregulated during osteoclastogenesis from both RAW 264.7 cells and primary human monocytes. We also demonstrated that inhibition of miR-99a-5p in MC3T3 increased the OPG / RANKL mRNA expression ratio and that the supernatant collected from these cells inhibited RAW 264.7 differentiation into osteoclasts. Additionally, results show that miR-99a-5p was differently expressed in a time-dependent manner in the bone marrow of rats upon a bone critical defect injury. Finally, results from bone osteoporotic human samples showed increased miR-99a-5p expression levels compared with osteoarthritis samples. Taken together, our data shows that miR-99a-5p is a critical regulator of osteogenic differentiation and suggest that modulation miR-99a-5p levels might be a strategy to re-establish bone homeostasis in fragile bones.
Osteoporose é uma doença crónica do esqueleto caracterizada pela perda de massa óssea e deterioração do tecido ósseo, que conduz a um aumento do risco da ocorrência de fraturas. A etiologia desta doença reside na desregulação entre a reabsorção (realizada pelos osteoclastos) e a formação (realizada pelos osteoblastos) óssea. Considerando o envelhecimento da população, espera-se um aumento do número de casos nos próximos anos, o que torna a osteoporose um grave problema de saúde pública e uma das principais causas de morbidade e mortalidade, principalmente devido às fraturas de fragilidade às quais estão frequentemente associadas. Atualmente, os tratamentos para a osteoporose consistem predominantemente em drogas que inibem / previnem a reabsorção óssea, mas podem ter vários efeitos secundários associados. Portanto, a necessidade de novas abordagens que promovam a homeostasia do osso e a regeneração de fraturas em pacientes diagnosticados com osteoporose está a aumentar. Nos últimos anos, os microRNAs (miRNAs), uma classe de pequenos RNAs que não codificam proteína e que são importantes reguladores da expressão génica, estão a ganhar cada vez mais relevância como reguladores de mecanismos celulares. Estudos recentes têm vindo a revelar o seu papel na patogénese de várias doenças, entre as quais a osteoporose. Neste contexto, o principal objetivo deste estudo foi investigar o papel do miR-99a-5p na diferenciação osteogénica, um processo necessário e indispensável para a formação e regeneração óssea. Além disso, explorou-se o perfil de expressão deste microRNA na osteoclastogénese, durante a regeneração de fraturas ósseas e em pacientes com osteoporose. Para atingir estes objetivos, começamos por avaliar o perfil de expressão do miR-99a-5p durante a diferenciação osteogénica, tanto na linhagem celular MC3T3, como em células mesenquimais do estroma humanas (MSC), por transcrição reversa - reação em cadeia da polimerase quantitativa em tempo real (RT-qPCR). Em seguida, para analisar o efeito biológico do miR-99a-5p na osteogénese e na proliferação, foram realizadas transfeções in vitro de oligonucleótidos que mimetizam ou inibem o efeito do miR-99a-5p. Com intuito de identificar quais os alvos e vias moleculares afetadas e controladas pelo miR-99a-5p, investigámos o perfil de proteínas expressas pelas células transfetadas com anti-miR-99a-5p em comparação com o controlo. Para além disso, o perfil de expressão do miR-99a-5p foi também estudado durante a osteoclastogénese da linha celular RAW 264.7 e de monócitos humanos, bem como o efeito do meio condicionado das células MC3T3 transfetadas na osteoclastogénese. Por fim, determinou-se a expressão do miR-99a-5p durante o processo de regeneração óssea num modelo animal e em pacientes que sofreram fraturas de fragilidade/osteoporóticas. Os resultados obtidos demostraram que o miR-99a-5p é significativamente subexpresso durante a diferenciação osteogénica das MC3T3 e durante as fases iniciais da diferenciação osteogénica das MSCs humanas. A sobreexpressão do miR-99a-5p na linha celular pré-osteoblástica MC3T3 resultou numa diminuição dos marcadores de diferenciação osteogénica enquanto que a sua inibição aumentou a expressão dos mesmos marcadores osteogénicos, entre os quais da fosfatase alcalina. Verificou-se ainda que a modulação dos níveis do miR-99a-5p na linhagem celular MC3T3 não afetou a proliferação celular. A análise proteómica dos lisados celulares provenientes das MC3T3 em que a expressão do miR-99a-5p foi inibida, comparativamente ao controlo, mostrou que diversas proteínas, conhecidas por estarem envolvidas na diferenciação osteogénica, se encontravam alteradas, como a plexin-A2 (PLXA2), all-trans retinoic acid-induced differentiation factor (ARAID), ARF GTPase-activating protein GIT (GIT1) and Ephrin type-A receptor 2 (EPHA2). Os resultados mostraram também que a inibição dos níveis do miR-99a-5p influenciam várias vias descritas como estando associadas à osteoporose, incluindo a Ephrin receptor, Pl3K-Akt e canonical Wnt. Em contraste com o perfil de expressão verificado durante a osteogénese, o miR-99a-5p encontra-se sobreexpresso ao longo da osteoclastogénese das RAW 264.7 e dos monócitos humanos. Demonstrámos também que a inibição do miR-99a-5p nas MC3T3 fomentou o aumento de expressão da razão OPG/RANKL ao nível do mRNA e que o sobrenadante recolhido a partir dessas células inibe a diferenciação das RAW 264.7 em osteoclastos. Adicionalmente, os resultados mostram que a expressão do miR-99a-5p varia ao longo do tempo na medula óssea de ratos após uma lesão óssea de defeito crítico. Finalmente, os resultados obtidos a partir de amostras humanas de pacientes com fractura de fragilidade e diagnosticados com osteoporose mostraram que estes apresentam níveis mais elevados de expressão do miR-99a-5p comparativamente ao controlo (amostras de pacientes com osteoartrite). Tendo em conta os resultados obtidos ao longo deste trabalho, concluímos que o miR-99a-5p é um regulador crítico da diferenciação osteogénica. No futuro, a modulação dos níveis do miR-99a-5p no osso pode ser utilizada como uma estratégia que tem como objetivo restabelecer a homeostase óssea.

Osteogenesis imperfecta, innate brittle bone disease, is a very serious disease. It is inheritable disease of connective tissue, which shows by abnormal fragility of bones. The occurrence of this disease is one case in 10 000 30 000 births. The theoretical part of the thesis deals with the disease itself, also the psychical impact on children suffering from Osteogenesis imperfecta and the impact on their families as well. At the beginning of the research, three goals of this thesis were set: map out (on the basis of theoretical and practical backgrounds) the pitfalls of life of children with the disease Osteogenesis imperfecta, find out what are the most common difficulties by children with the disease Osteogenesis imperfecta and also find out the experiences of nurses with the care for children with disease Osteogenesis imperfecta. The empirical part of the thesis was processed by means of qualitative research conducted by the technique of semi-structured interview and narrative biographical interview. The research set were nurses working at the child departments in hospitals, parents of ill children and also an adult woman with the diagnosis of Osteogenesis imperfecta and two doctors. From the research emerged that among the most common difficulties of children is pain, which decreases the quality of their life. Small children can't engage in typical activities of children, such as going to a playground, older children can't attend for example music festivals. Children feel fear from fractures and are therefore limited in sports. Because of injuries and their treatments, the children have more absences at schools and therefore are isolated from peers. Nevertheless, the children with this disease can live a happy life. From the results of the research also emerges, that nurses working at the child departments of the hospitals attended by children with this illness have a good experiences with their treatment. They are able to give parents important information and know the specifics of application of the treatment. The results of the diploma thesis were presented at a national student conference and will be further published.

Dissertação de Mestrado em Evolução e Biologia Humanas apresentada à Faculdade de Ciências e Tecnologia
A osteoporose é uma desordem óssea metabólica de etiologia multifatorial caracterizada pelo decréscimo da massa óssea, pela deterioração da microarquitectura e pelo consequente aumento do risco de fratura. As mudanças diacrónicas dos fatores etiológicos como os hábitos alimentares, a longevidade ou as mudanças na atividade física poderão ter conduzido a diferenças na prevalência da osteoporose e das fraturas que lhe estão, epidemiologicamente associadas (como as fraturas de compressão das vértebras; fraturas do fémur proximal; fraturas do rádio distal e fraturas do úmero proximal) ao longo do tempo. O Objetivo deste trabalho foi a identificação do padrão de perda de massa óssea cortical e a sua relação com fraturas de fragilidade numa amostra esquelética pertencente à Coleção de Esqueletos Identificados (meados do século XIX/ inícios do século XX) e a sua comparação com os padrões de perda de massa óssea e de prevalência de fraturas de fragilidade numa coleção esquelética de referência pertencente aos séculos XX e XXI (Coleção de Esqueletos Identificados do século XXI [CEI/XXI]). Os resultados foram obtidos através da mensuração radiogramétrica dos parâmetros corticais no segundo metacárpico e da identificação macroscópica e radiográfica das fraturas de fragilidade (vértebras, fémur proximal, rádio distal e úmero proximal) numa amostra esquelética pertencente à Coleção de Esqueletos Identificados da Universidade de Coimbra (CEI), séculos XIX e XX (N=302). Os resultados obtidos sugerem que a massa cortical diminui com a idade à morte em ambos os sexos, mas principalmente no sexo feminino. Na comparação das duas amostras CEI e CEI/XXI o padrão de perda de massa óssea parece ser semelhante no grupo feminino mas não para o masculino, tendo sido observado um menor «Índice de Massa Cortical» nos indivíduos masculinos amostrados da CEI/XXI. As fraturas de fragilidade relacionam-se com o aumento da idade e com a redução da massa óssea, não tendo existido diferenças significativas entre os sexos na maior ou menor prevalência destas. Após a comparação das duas amostras, também, não foram observadas diferenças significativas na prevalência de fraturas de fragilidade. Contudo, os resultados demonstram que existia a prevalência de fraturas fragilidade no passado, tendo uma maior incidência nas faixas etárias mais velhas não sendo apenas influenciadas pela massa óssea, mas também por outros fatores.
Osteoporosis is a metabolic bone disease of multifactorial etiology characterized by decreased in bone mass, deterioration of bone microarchitecture and increasing risk of fracture. The diachronic changes of etiological factores such as eating habits, longevity or changes in physical activity may have led to differences in the prevalence of osteoporosis and fractures epidemiologically associated to that disease (e.g. hip fractures, vertebral fractures and distal radius fractures) over time. The aim of this study was the identification of cortical bone loss and its relationship to fragility fractures in two identified skeletal collections housed at the University of Coimbra. The studied sample belong to The Coimbra Identified Skeletal Collection (CISC – 19th-20th) of the University of Coimbra wich was compared with another sample that belongs to The 21st Century Identified Skeletal Collection (CEI/XXI) of the University of Coimbra. The results were obtained by radiogrammety measurement of cortical parameters in the second metacarpal and by macroscopic and radiographic identification of fragility fractures (vertebrae, proximal femur, distal radius and proximal humerus) in 302 skeletons from CEI.The results suggested that cortical mass decreases with age in both sexes, but especially in females. After comparing the two samples (CEI and CEI/XXI) the patterns of bone loss appears to be similar in women but not for the male group. Males from CEI/XXI show a lower “Cortical Mass Index” relatively to CEI male sample. The fagility fractures are related to aging and reduced bone mass, with no significant differences between the two sexes. After comparing the two samples no significant differences, in the prevalence of fragility fractures, were observed as well. However, the results revealed that there was a prevalence of fragility fractures in the past, with higher incidence in older age groups. This incidence appears to have been influenced, not only by bone mass, but also by other factors.

O objetivo principal deste estudo foi analisar a relevância do salto horizontal como marcador de fragilidade óssea em contexto escolar em crianças e jovens dos 10 aos 17 anos. Metodologia: A amostra incluiu 477 participantes, de ambos os géneros (220 raparigas e 257 rapazes). A fragilidade óssea foi identificada a partir de densitometria radiológica de dupla energia (DXA) através de um exame de corpo inteiro, sem a cabeça. Para as devidas comparações, os participantes foram divididos em 2 grupos de acordo com Z-Score da densidade mineral óssea( DMO) subtotal (< -0,9 DP vs. ≥ - 0,9 DP). A aptidão muscular foi avaliada através de salto horizontal realizado com e sem pausa na preparação da impulsão para o salto, com a finalidade, dos seus valores serem comparados com jovens de outros países. A análise do poder preditor do salto horizontal para identificação da fragilidade óssea, foi efetuada através de regressão logística. Resultados: Nas raparigas foi observado que o aumento de 1DP no salto horizontal estava associado a uma diminuição da probabilidade de fragilidade óssea em 43-45% (p<0,05), consoante se considera o salto com pausa e sem pausa, respetivamente. Nos rapazes não foi observado qualquer poder preditor do salto horizontal para a identificação da fragilidade óssea. Conclusão: A aptidão muscular avaliada através do salto horizontal pode constituir um marcador da fragilidade óssea nas raparigas mas não nos rapazes dos 10 aos 17 anos.
The main objective of this study was to analyze the relevance of horizontal jump as a marker of bone fragility in school context in children and young people from 10 to 17 years. Methodology: The sample included 477 participants of both genders (220 girls and 257 boys). Bone fragility was identified from dual energy radiological densitometry (DXA) through a full body examination without the head. For proper comparisons, participants were divided into 2 groups according to Z-Score of subtotal bone mineral density (BMD) (<-0.9 SD vs. ≥ -0.9 SD). Muscle fitness was assessed by horizontal jump performed with and without pause in the preparation of the jump impulse, with the purpose of comparing their values with young people from other countries. Predictive power analysis of horizontal jump to identify bone fragility was performed by logistic regression. Results: In girls it was observed that the 1DP increase in horizontal jump was associated with a 43-45% decrease in the likelihood of bone fragility (p <0.05), depending on whether paused and non-paused jumping, respectively. In boys, no predictive power of horizontal jump was observed to identify bone fragility. Conclusion: Muscle fitness assessed through horizontal jump may be a marker of bone fragility in girls but not boys aged 10 to 17 years.

Objetivo: Analisar as associações entre a potência muscular dos membros inferiores e a saúde óssea avaliada através de ultrassonografia quantitativa. Métodos: A amostra incluiu 63 crianças de 9 anos de idade. A velocidade de som (VS) do rádio e da tíbia foi avaliada através de ultrassonografia quantitativa, a potência de salto foi estimada a partir de um salto vertical com contramovimento e a maturidade somática foi determinada a partir da estimação do pico de velocidade em altura. O estado geral de saúde e o historial de fraturas foram avaliados através de questionário. As associações entre medidas dos parâmetros ósseos e a potência de salto foram analisadas através de correlações bivariadas, com as variáveis expressas em valores absolutos e relativos (estandardizados). Resultados: Foram observadas associações positivas entre a maturidade somática e a potência de salto expressa tanto em valores absolutos como relativos (p <0,05). A maturidade somática correlacionou-se ainda positivamente com a VS da tíbia nas raparigas (r=0,358, p=0,045), enquanto nos rapazes se verificou uma associação negativa, embora não significativa (r=-0,290, p=0,126). Observou-se uma associação ou propensão para associação negativa entre a VS da tíbia e a potência de salto nos rapazes (r=-0,490, p=0,007) e nas raparigas (r=-0,344, p=0,054). Conclusão: A potência de salto não parece constituir um bom marcador da saúde óssea de rapazes e raparigas de 9 anos de idade quando avaliada através de ultrassom.
Objective: To analyze the association between the muscle power of the lower limbs and bone health assessed by quantitative ultrasound. Methods: The sample includes 63 children with 9 years old. The speed of sound (VS) of the radius and tibia was assessed by quantitative ultrasound, jump power was estimated from a vertical jump with countermovement and somatic maturity was determined from the estimation of the peak velocity in height. The general health and history of fractures were assessed by questionnaire. Associations between measurements of bone parameters and the jump power were analyzed using bivariate correlations, with the variables expressed in absolute and relative values (standardized). Results: Positive associations were observed between somatic maturity and jump power expressed in absolute and relative values (p <0.05). The somatic maturity also correlated positively with the SV of the tibia in girls (r = 0.358, p = 0.045) while in males there was a negative association although not significant (r = -0.290, p = 0.126). There was an association or propensity for negative association between VS tibia and jump power in boys (r = -0.490, p = 0.007) and in girls (r = -0.344, p = 0.054). Conclusion: The power of the vertical jump does not seem to be a good marker of bone health in boys and girls with 9 years old when this is assessed by ultrasound.

Le β-talassemie sono un gruppo di malattie del sangue ereditarie caratterizzate da una ridotta o assente sintesi di β-globina, con fenotipi variabili che vanno da una grave anemia ad individui clinicamente asintomatici. Il ritardo di crescita si osserva frequentemente e fratture da fragilità sono comuni in questi pazienti. L'osteoporosi colpisce circa il 51% dei pazienti e circa il 45% l' osteopenia.⁠ Negli ultimi anni, i ricercatori hanno focalizzato l'attenzione su un gene chiamato α-Klotho (Klotho). Il gene Klotho codifica per una proteina che si esprime in reni, ghiandole paratiroidi e plesso coroideo. Topi knock-out sviluppavano un fenotipo da 'invecchiamento' che comprendeva, tra le altre condizioni, riduzione della densità ossea, ritardo di crescita e ipogonadismo. La proteina è presente nel sangue, urine e nel liquido cerebrospinale ed è coinvolta nella omeostasi del calcio nel rene. Ci sono pochi studi clinici che collegano i livelli di Klotho secreto nel sangue periferico e soggetti umani. Nessuno in pazienti con β-talassemia. Lo scopo di questo studio è stato quello di analizzare le possibili correlazioni tra livelli plasmatici della proteina Klotho e l'osteoporosi, scarsa forza muscolare e fratture, nei pazienti con β-talassemia major. Un totale di 106 pazienti con β-talassemia major e 95 donatori di sangue sani sono stati arruolati. I pazienti con β-talassemia major avevano un minor livello di Klotho rispetto ai controlli sani. Klotho era più basso nei pazienti con osteopenia / osteoporosi. Inoltre, un basso livello di proteina ​​aumenta la probabilità di frattura da fragilità. La forza muscolare è direttamente correlata I livelli di Klotho (fino a 580 pg/ml). Questa analisi suggerisce che età o addirittura malattie legate all mancanza di Klotho, possono giocare un ruolo chiave nella catena di eventi che portano a sarcopenia e osteoporosi, componenti della sindrome da dismobilità. Inoltre, questo studio identifica Klotho come un potenziale fattore di rischio per sindromi da dismobilità e la sua complicazione clinicamente rilevante, cioè fratture da fragilità.
β-thalassemia syndromes are a group of hereditary blood disorders characterized by reduced or absent β-globin synthesis, resulting in variable phenotypes ranging from severe anemia to clinically asymptomatic individuals. Growth retardation is observed frequently and fragility fractures are common in these patients. Osteoporosis affects approximately 51% of the patients with another 45% suffering from osteopenia. In recent years, researchers have focused the attention on a gene called α-Klotho (Klotho). The Klotho gene encodes a protein that is expressed in kidney, parathyroid gland and choroid plexus. Klotho protein is present in blood, urine and cerebrospinal fluid and it is involved in calcium homeostasis in the kidney. Re-absorption of calcium in the distal tubule of the kidney. knock-out mutants for the gene. These animals developed an 'aging' phenotype which included, among other conditions, reduced bone density, growth retardation, hypogonadism There are very few clinical studies that link the levels of secreted Klotho in peripheral blood and phenotype in humans and none of them in β-thalassemia subjects. Aim of this study was to analyze possible correlations between plasma level of Klotho protein and osteoporosis, poor muscle strength and fractures in patients with β-thalassemia major. A total of 106 β-thalassemia major patients and 95 healthy blood donors were enrolled. Patients with β-thalassemia major had lower level of Klotho than healthy controls. Klotho was lower in patients with osteopenia/osteoporosis. Moreover, a low level of protein increased the probability of fragility fracture. The muscle strength was found directly correlated to Klotho (up to 580 pg/ml). This analysis suggests that age- or even a disease-related decrease of Klotho may play a key role in the chain of events producing sarcopenia and osteoporosis, components of the dysmobility syndrome. Furthermore, this study identifies Klotho as a potential risk factor for dysmobility syndrome and its clinically relevant complication, namely fragility fractures.